Japanese traditional Kampo medicine bofutsushosan improves body mass index in participants with obesity: A systematic review and meta-analysis

Background The number of people with obesity is rapidly increasing worldwide. Since obesity is a critical risk factor for cardiovascular diseases and mortality, the management of obesity is an urgent issue. However, anti-obesity drugs are insufficient in current clinical settings. Bofutsushosan (BTS, Fang-Feng-Tong-Sheng-San in China) is a traditional Japanese Kampo formula for patients with obesity. Recent basic studies have indicated that BTS potentially improves the pathophysiology of obesity. However, it is still unknown whether BTS clinically reduces body mass index (BMI) in patients with obesity. Methods We searched electronic databases, including the Medline, EMBASE, Cochrane Library, and Japanese/Chinese/Korean databases, on June 15, 2021. We conducted a meta-analysis of randomized controlled trials to evaluate the effects of BTS on BMI, waist circumference, glycolipid metabolism, and blood pressure in participants with obesity. The primary outcome was change in BMI. Results We included seven studies and 679 participants (351 in the BTS group and 328 in the control group). In participants with obesity, BTS significantly reduced BMI relative to controls (mean difference, MD [95% confidence interval]: −0.52 kg/m2 [−0.86, −0.18], P = 0.003). There was no significant difference in waist circumference, glycolipid parameters, or blood pressure. Sensitivity analyses showed robust outcomes for the primary endpoint, although the heterogeneity was considerable. Moreover, no serious adverse events were observed in the BTS group. Conclusion BTS showed a potential benefit in safely and tolerably improving BMI in participants with obesity.


Study selection
Two independent authors (KU and YK) selected studies through the following procedure. First, KU and YK extracted studies from electronic databases and screened their titles and abstracts independently. Second, the two authors reviewed the full text of all qualified studies according to inclusion and exclusion criteria in a blinded fashion. If any discrepancies occurred between the two authors, a third author (TY) tried to resolve them.
Inclusion criteria were described as follows: (i) patients with obesity (�18 years old); (ii) RCT comparing an intervention group treated with BTS and a control group; (iii) reported data on BMI, waist circumference, glycolipid metabolism (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], triglycerides [TG]), and blood pressure between groups. Exclusion criteria were shown as follows: (i) animal experiments and (ii) lack of BMI data (even after contacting the authors). We only included studies written in English, Japanese or Chinese.

Data extraction and quality assessment
After study selection, two reviewers (KU and YK) extracted data regarding BMI, waist circumstance, glycolipid metabolism, and blood pressure in the treatment and control groups from each study. We used the Cochrane risk of bias assessment to assess the degree of bias in our meta-analysis, focusing on the following factors: random sequence generation, allocation concealment, blinding of participants and researchers, blinding of outcome assessments, selective reporting, incomplete outcome data, and other metrics [28]. A third reviewer (TY) corrected any discrepancies regarding data extraction or quality assessment.

Endpoints of meta-analysis
The primary endpoint was the absolute change in body mass index. The secondary endpoints were absolute change in waist circumstance, glycolipid metabolism, and blood pressure.
confidence intervals (CI) were estimated for statistical analysis using a random effects model [29]. Additionally, we performed sensitivity analyses for the robustness of our findings. Heterogeneity between studies was evaluated using Cochran's Q test and I-squared (I 2 ). P values < 0.05 indicated statistical significance. I 2 values � 75% represented considerable heterogeneity among the included studies [30,31]. Moreover, we evaluated publication bias visually based on the symmetry of funnel plots.

Literature search and listed studies
Our study selection procedure is shown in Fig 1. A total of 362 studies were identified following the database search. Furthermore, seven studies were added after reviewing the reference lists of these articles. After removing duplicate studies, we screened the titles and abstract of 263 studies and excluded 254 studies. Next, we assessed the full text of the remaining nine records and removed two articles because of insufficient data. Finally, seven studies were included in our meta-analysis [19-21, 25, 32-34]. All studies were conducted as randomized controlled trials (RCTs) of BTS for participants with obesity. All studies included BMI as an outcome. Table 1 lists the seven studies included in our analysis. Five studies were conducted in Japan, and the others were conducted in China and Korea. Three studies were double-blind

PLOS ONE
placebo-controlled RCTs, whereas the others were open-label studies. One study compared BTS and another Kampo medicine, daisaikoto (dachaihutang in China). Another trial investigated the effects of adding BTS therapy to metformin treatment [21]. Three studies were performed for eight weeks, and the others were performed for 24 weeks. There was some variation in the dose of crude drugs of BTS among studies (S1 Table). Six studies defined the cut-off value of obesity as 24 or 25 kg/m 2 ; one study did not mention a definition of obesity.

Study characteristics and quality assessment
The baseline characteristics of participants in the included studies are summarized in Table 2. There were 679 participants (351 in the BTS group and 328 in the control group). The mean age of participants was 53.8 years, and more than half were female. The mean BMI was 30.6 kg/m 2 . The average glycohemoglobin, LDL-C, TG, and blood pressure levels were 5.6%, 133.8 mg/dL, 166.8 mg/dL, and 136.8/84.7 mmHg, respectively. Fig 2 showed the risk of bias for the included studies. Generally, selection bias was evaluated as "low risk," although more than half of the studies had an unclear risk of bias. Performance bias was relatively high because half of the studies were planned as an open-label RCT. We could not find any publication bias in our study (S1 Fig).

Efficacy of BTS for BMI and waist circumference
We conducted a meta-analysis of all participants who completed the included studies.

Influence of BTS on glycolipid metabolism and blood pressure
Next, we evaluated the effects of BTS on glycolipid metabolism in participants with obesity. BTS did not significantly reduce free blood glucose (FBG)/glycohemoglobin levels relative to    (Fig 5). There was a considerable heterogeneity in HDL-C (I 2 = 79%, P = 0.007). Additionally, Fig 6 shows

Sensitivity analyses for BMI
For robust assessment, we performed sensitivity analyses for the primary outcome (Table 3)  . Fourth, we considered the laxative effect of BTS on BMI reduction. Among the crude drugs of BTS, Rhei Rhizoma, a traditional laxative, could affect participants' BMI. In our study, three trials by Hioki, Xu, and Murase adopted placebos containing laxative components. Thus, we performed a sensitivity analysis to compare the BTS and these three groups. There was a significant BMI improvement in the BTS group relative to the controls using laxative placebos (MD [95% CI]: -0.85 kg/m 2 [−1.64, −0.06], P = 0.03) with considerable heterogeneity (I 2 = 85%, P = 0.001). Finally, we focused on the contents of BTS. One study [21] used a BTS extract with a higher dose of crucial drugs than that in the other studies (S1 Table). We

Adverse effects of BTS
The adverse effects of BTS are summarized in Table 4. Gastrointestinal symptoms were observed in 4.84% (17/351) of participants in the BTS group and 2.13% of participants (7/328) in the control group. Notably, no serious events were reported in either group.

Discussion
We present here the first meta-analysis to indicate the efficacy of BTS for improving BMI in obese participants. BTS is a traditional Kampo medicine for patients with visceral fat obesity in Japan [35]. In our study, BTS had some variation in the crude drug components. Particularly, the dose of crude drugs used in Wu's study was higher than that in other studies [21]. However, our sensitivity analysis excluding Wu's study showed that BMI in the BTS groups decreased significantly compared with that in the control groups. Moreover, in another sensitivity analysis, BTS improved BMI compared to placebos containing laxative ingredients. Our results demonstrate that BTS is one of the new pharmacologic options for treating obesity. Previous studies reported that BTS reduced visceral fat in experimental animals and patients [24,36]. In our study, BTS did not lead to a significant waist circumference reduction. Further investigations are needed to clarify the efficacy of BTS in visceral fat reduction. Previous basic studies have shown the weight loss effect of BTS through several mechanisms [24,[37][38][39]. Among the components of BTS, Ephedrae Herba, Glycyrrhizae Radix, Schizonepetae Spica, and Forsythiae Fructus promoted brown fat thermogenesis and white fat lipolysis in experimental animals [24,37,40,41]. One clinical trial also suggested an increase in fat consumption induced by BTS treatment [36]. Moreover, BTS showed potential appetite-suppressant activity through regulating the ghrelin system [24]. Taken together, these mechanisms of BTS exerted a possible effect leading to the improvement in BMI shown in our study.
The changes in glycolipid metabolism between the BTS and control groups were not significantly different in our study. Past studies have reported that BTS improves impaired glucose tolerance and dyslipidemia in experimental animals and patients [33,39,42]. The mild abnormality of participants' baseline glycolipid parameters may influence the results of our meta- analysis. Further studies on the effects of BTS on glycolipid metabolism in obese patients with diabetes and dyslipidemia are warranted. Similarly, there was no significant difference in blood pressure changes between both groups in our study. We could not find any clinical research reporting BTS lowering blood pressure, including our study. However, BTS improved hypertension, as well as body weight, in experimental obese animals [24,39]. Further investigations are needed to explain the discrepancy in BTS's effects on blood pressure in obesity between basic and clinical research. Several anti-obese agents can currently be prescribed in clinical settings [11][12][13]43]. However, these agents have some problems, such as side effects and administrationform. Mazindol, phentermine/topiramate, and naltrexone/bupropion suppress patients' appetite and exert a weight loss effect [15,44,45]. However, these drugs are related to psychiatric adverse events, such as insomnia, anxiety, and hallucination [15,43,44,46]. Orlistat is also an available antiobesity agent. Because orlistat inhibits intestinal lipases and improves obesity, several gastrointestinal side effects, such as diarrhea or oily stool, are reported in 15-30% of participants in past trials [17]. Liraglutide, one of the representative glucagon-like peptide 1 (GLP-1) receptor agonists, exerts favorable effects on obesity and cardiovascular disease [47][48][49]. However, liraglutide is an injectable drug and has a possibility of mild gastrointestinal adverse events [43,48,49]. In contrast, BTS, an oral Kampo medicine, showed no serious adverse events in our study (Table 4). There were few reports of diarrhea, even though BTS contains Rhei Rhizoma, a traditional laxative. Therefore, these points proved the safety and good tolerability of BTS.
In our study, some limitations were observed. First, the risk of bias for some included studies was relatively high. Second, the heterogeneity related to the primary outcome was generally high. No significant heterogeneity was observed in the sensitivity analysis, including only participants with higher baseline BMI levels. Therefore, variation in participants' baseline characteristics of BMI levels may be related to heterogeneity in our study. Third, most participants in our study were East Asians. Because previous reports have suggested the cut-off points for obesity in Asians are lower than those in other ethnicities [13], further multinational trials are warranted to investigate the anti-obesity effects of BTS.

Conclusion
BTS safely and tolerably exerted a potential benefit to reduce BMI in participants with obesity.